TTR Levels Research Articles

Molecular analysis of the expression of transthyretin in intestine and liver from trisomy 18 fetuses.

Human trisomy 18 (Edwards syndrome) provides a model for the role that genes on chromosome 18 play in fetal development. Trisomy 18 occurs in approximately 1 in 3000 live births. Despite its compatibility with life in 5% of cases, prolonged survival is rare. Anomalies involve the urogenital, cardiac, craniofacial and central nervous systems. The abnormalities could be caused by the abnormal expression of developmentally important genes on chromosome 18. We have investigated the quantity and localisation of the expression of a candidate gene, transthyretin (TTR), on chromosome 18 at the RNA level in intestine and liver tissues from trisomic fetuses and have compared the expression with normal age-matched fetal tissues. The mRNA level of TTR in 10 to 14-week intestine was the same in trisomy 18 and control tissues. However, overexpression was seen for both trisomy 18 liver and intestine at 20-23 weeks. TTR transports both thyroxine and retinol and is therefore important for normal fetal development.

Efficacy of massive oral doses of retinyl palmitate and mango (Mangifera indica L.) consumption to correct an existing vitamin A deficiency in Senegalese children.

Administration of large oral doses of retinyl palmitate has become the most widely practised vitamin A deficiency prevention strategy in developing countries. We conducted a follow-up study among 220 Senegalese children aged 2-7 years suffering from moderate undernutrition to determine the efficacy of vitamin A treatment on their vitamin A status assessed by biochemical and cytological (impression cytology with transfer) methods. The first examination (T = 0 m[onth]) was carried out during April 1989, before the mango (Mangifera indica L,) harvest. The second examination (T = 2 m) was carried out 2 months after vitamin A treatment during June 1989 when ripe mangoes become widely available. Conjunctival cells of the eyes of the children with or without ocular inflammation were responsive to vitamin A administration (P < 0.01). There was a significant increase (P < 0.001) in mean serum retinol and beta-carotene levels between T = 0 m and T = 2 m. Mean serum retinol-binding protein (RBP) and transthyretin (TTR) levels did not differ significantly (P > 0.05) at T = 0 m and T = 2 m. Despite the intake of vitamin A, 54% of the children who had abnormal cytology at T = 0 m remained abnormal at T = 2 m. This was due to inadequate levels of TTR and RBP, presumably due to the cereal diet eaten by the Senegalese population. children with abnormal eye cytology had lower serum retinol levels than those with normal eyes at T = 0 m, and beta-carotene values did not correlate with eye cytological abnormalities at T = 0 m. Children with normal cytology had higher serum retinol and also beta-carotene levels than those with abnormal cytology after massive oral doses of vitamin A and consumption of mangoes at T = 2 m. Retinyl palmitate may, therefore, only lead to partial cytological improvement due to a lack of retinol-carrier proteins but dietary beta-carotene may also be involved.

Failure of Tryptophan Deficiency to Reduce Specifically Serum Levels of Transthyretin or Albumin in Rats

Because transthyretin (TTR) is a tryptophan-rich molecule and a sensitive nutritional marker, tryptophan deficiency might markedly influence the circulating level of TTR. The effect of severe tryptophan (Trp) deficiency on serum TTR, as well as on albumin and transferrin levels, was studied in growing rats for 8 d. The animals were then refed a control diet for 12 d. The Trp-deficient and control diets contained 0.008 and 0.34% Trp, respectively. A loss of body weight and a dramatic reduction in food intake were observed in the Trp-deficient rats. Although serum total Trp concentration was significantly less in these rats than in pair-fed controls, serum TTR declined to the same extent in both groups compared to control rats fed ad libitum. Albumin concentrations were not altered, but transferrin levels declined slightly in the Trp-deficient rats compared to both the pair-fed group and the controls fed ad libitum. Refeeding the control diet to Trp-deficient rats restored total and free Trp concentrations, as well as TTR and transferrin levels, but body weight and food intake remained lower than in the control group. To examine the effect of moderate Trp restriction, rats were fed for 2 wk a diet whose Trp content was 50% less than that of the control diet. Although total and free Trp concentrations were significantly lower in the rats fed the Trp-deficient diet than in the control group, body weight, food intake and TTR levels were similar in both groups. The results suggest that acute and severe Trp deficiency per se does not modify TTR and albumin levels.

Plasma retinol transport system and taste acuity in patients with obstructive jaundice

A study was conducted to elucidate the correlation between the plasma retinol transport system and taste acuity in patients with obstructive jaundice (OJ). Plasma levels of retinol, retinol-binding protein (RBP), transthyretin (TTR) and holo-RBP (retinol-RBP complex unbound to TTR), as well as the threshold of taste acuity, were determined in 8 cases with OJ (6 cases with common bile duct cancer and 2 cases with pancreas head cancer) and in 20 apparently healthy volunteers. These parameters were also measured serially in patients with OJ before and after percutaneous transhepatic biliary drainage (PTBD). Plasma levels of retinol, RBP and TTR were significantly decreased in every patients with OJ as compared with healthy controls, whereas changes in holo-RBP levels were not consistent. Taste acuity was found to be reduced in patients with decreased holo-RBP levels, while the acuity was preserved well in patients whose holo-RBP levels remained normal. Impaired taste acuity was rapidly improved in every patients after treatment with PTBD, significantly correlating with the recovery of plasma RBP and holo-RBP levels, and with the reduction of plasma total bilirubin levels. These results suggest that taste acuity is affected by the plasma retinol transport system, including serum levels of holo-RBP, from which retinol is delivered, presumably through a receptor-mediated manner, to the taste buds.

Combined effects of moderate feed restriction and acute inflammation on rat serum transthyretin

The combined effects of moderate feed restriction and acute inflammation on serum transthyretin (TTR) levels were studied in five groups of 4-week-old male Wistar rats fed a 18% protein diet. Two groups were fed ad libitum: the control (C) and turpentine (T) groups while 2 others were given the diet in restricted amounts: the restricted (R) and restricted and turpentine-injected (RT) groups. After 18 days on the experimental diets, groups T and RT were injected with turpentine (0.5 ml/100g body weight). A fifth group, previously fed ad libitum was then pair-fed to group T for 48h (group PF). Groups T and RT were killed 48h following turpentine administration together with group R while group PF was killed 24h later. Half of the control group was killed with the four former groups and half with the latter. Orosomucoid levels were dramatically enhanced in the groups T and RT and were not affected by food restriction. Transferrin levels were decreased in group R and only very slightly increased by acute inflammation. TTR concentration fell by 65% in group T; twenty-one percent of this decrease resulted from the associated reduction in food intake. The specific effect of inflammation on TTR level was similar when calculated from the difference between the values obtained in groups PF and T on the one hand and between groups R and RT on the other hand. The results suggest that when moderate feed restriction and acute inflammation are associated, total decrease in serum TTR levels is the sum of the individual drops induced by the nutritional and the inflammatory insults.

Diagnostic radioimmunoassay for familial amyloidotic polyneuropathy before clinical onset.

The purpose of this study is to develop an early diagnostic method for familial amyloidotic polyneuropathy (FAP) before clinical manifestations appear around the age of 30 yr. Amyloid fibrils isolated from type I FAP (FAP1) of Portuguese, Swedish, and Japanese origins consist of a variant transthyretin (TTR) that contains a methionine-for-valine substitution at position 30 or a mixture of normal TTR and this variant form. The variant TTR is present in the serum of FAP1 patients and can be measured by a radioimmunoassay (RIA) based on a nonapeptide (positions 22-30) derived from the variant TTR. Serum levels of the variant TTR in 45 Japanese FAP1 patients range from 4.71 to 17.61 mg/dl with a mean value of 9.18 mg/dl. The variant TTR is not present in the serum of 100 normal individuals, in four cases of primary and six cases of secondary amyloidosis, nor in 26 non-inheriting members of families with FAP1. The variant TTR level is measured in 24 children of 15 FAP1 patients as well. The variant TTR is already present in nine symptom-free children with the mean serum level of 11.90 mg/dl, but it is not present in 15 other children. FAP1 patients can be differentiated from non-FAP by this noninvasive diagnostic method even within families. The RIA can be applied worldwide to this intractable disorder for early diagnosis during childhood and for appropriate genetic counseling.

Biochemical marker in familial amyloidotic polyneuropathy, Portuguese type. Family studies on the transthyretin (prealbumin)-methionine-30 variant.

A transthyretin variant with a methionine for valine substitution at position 30 [TTR(Met30)] is found in Portuguese patients with familial amyloidotic polyneuropathy (FAP). Effective, rapid, small- and semimicro-scale (immunoblotting) procedures were developed to determine whether or not TTR(Met30) is present in the plasma of an individual subject. The immunoblotting procedure employs only 0.10 ml of serum and can serve as a reliable procedure for the screening of large numbers of persons for the presence of TTR(Met30). In family studies of seven FAP kindreds, TTR(Met30) was found in 21 out of 41 asymptomatic FAP offspring, and its presence was not related to either age or sex. Thus, the mutant TTR segregated in accordance with the known autosomal dominant mode of inheritance of FAP. Total plasma TTR levels were not reduced in asymptomatic FAP offspring who were carriers of TTR(Met30), and no difference was observed between carriers and noncarriers of the mutant TTR. The ratios of the variant to normal TTR in plasma were estimated in asymptomatic FAP offspring and were similar to those found in FAP patients. In contrast, TTR(Met30) was relatively enriched in cerebrospinal fluid samples from two FAP patients. The significance of this finding is not known, but might relate to the preferential deposition of amyloid in the nervous system in FAP. A limited study was conducted involving simultaneous analysis of both stored (collected in 1975) and fresh serum from 20 FAP offspring, all of whom had been asymptomatic in 1975. In every subject, the results obtained with the stored and the fresh serum samples were in agreement. Six of these subjects developed clinical FAP since 1975; TTR(Met30) was present in each of these subjects. These several studies strongly suggest that the presence of TTR(Met30) in plasma constitutes a predictive biochemical marker of FAP in the preclinical phase of the disease.